CN106539799B - A kind of medicine for treating colitis and its purposes in the medicine for preparing treatment colitis - Google Patents
A kind of medicine for treating colitis and its purposes in the medicine for preparing treatment colitis Download PDFInfo
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- CN106539799B CN106539799B CN201610970071.3A CN201610970071A CN106539799B CN 106539799 B CN106539799 B CN 106539799B CN 201610970071 A CN201610970071 A CN 201610970071A CN 106539799 B CN106539799 B CN 106539799B
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- medicine
- colitis
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- pharmaceutically acceptable
- colon
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
Abstract
The present invention relates to a kind of medicine for treating colitis, the medicine includes the compound or its stereoisomer, geometric isomer, dynamic isomer, pharmaceutically acceptable salt shown in following formula, and pharmaceutically acceptable carrier, excipient, diluent, assistant agent, medium or its combination：
Description
Technical field
The present invention relates to field of medicaments, specifically, the present invention relates to a kind of medicine for treating colitis and its in preparation
Treat the purposes in the medicine of colitis.
Background technology
Colitis is the term for describing colitis.There is the inducement of a variety of colitis, including infect, blood supply it is weak and
Autoimmune response.Colon wall has many layers.Have and be wrapped in outside and be responsible for digesting longitudinal direction extruding of the food along colon
Smooth muscle layer.Internal layer or mucous membrane contact with fluid and make water and electrolyte absorption is to help to solidify excrement.Mucous layer is colitis
Position occurs for disease, and bears colitis symptoms.
Colitis is the still uncertain chronic gut nonspecific inflammation disease of a kind of cause of disease and pathogenesis, it is now recognized that
The factors such as gut mucosal immune function disorder, infection, h and E take part in pathogenic process jointly.Initially use anti-inflammatory drug,
The medicine for suppressing immune system can be added if its is unsuccessful.In most of several cases, it may be necessary to perform the operation to remove
All or part of colon and small intestine.Treatment to ischemic colitis is initially supportive, is made using intravenous fluid
Intestines are stablized and prevent dehydration.If not recovering the blood supply enough to intestines, possible needs operation loses the part of blood supply to remove
Intestines.Current therapeutic strategy, which is conceived to, controls inflammation and adjusts immune, main to be treated using anti-inflammatory agent and immunosuppressive drug, but all the time
Efficient low present situation is not broken away from.
The content of the invention
It is an object of the invention to provide a kind of medicine for treating colitis.
In order to realize the purpose of the present invention, the present invention provides a kind of medicine for treating colitis, and the medicine includes following formula
Shown compound or its stereoisomer, geometric isomer, dynamic isomer, pharmaceutically acceptable salt, and pharmaceutically
Acceptable carrier, excipient, diluent, assistant agent, medium or its combination：
Wherein R1 is F, Cl, Br or I；R2 is F, Cl, Br or I.
Preferably, R1 is F.
Preferably, R2 is Br.
It is highly preferred that tablet, capsule, suppository or injection can be made in the medicine.
The present invention also provides purposes of the compound in the medicine for preparing treatment colitis,
Wherein R1 is F, Cl, Br or I；R2 is F, Cl, Br or I.
Preferably, R1 is F.
Preferably, R2 is Br.
It is highly preferred that the medicine can for the stereoisomer of the compound, geometric isomer, dynamic isomer,
Pharmaceutically acceptable salt, and pharmaceutically acceptable carrier, excipient, diluent, assistant agent, medium or its combination.
It is highly preferred that tablet, capsule, suppository or injection can be made in the medicine.
Unless otherwise indicated, all scientific and technical terminologies used in the present invention have with those skilled in the art of the invention's
It is generally understood that identical implication.All patents of the present invention and public publication are integrally incorporated this hair by reference
It is bright.
Term " treatment " any disease or illness as used in the present invention, refer to improvement disease in some of these embodiments
Disease or illness (slow down or prevent or mitigate disease or the development of its at least one clinical symptoms).In other embodiments
In, " treatment " refers to mitigation or improves at least one body parameter, including the body parameter that may not be discovered by patient.Another
In a little embodiments, " treatment " refers to from body and (for example stablizes perceptible symptom) or physiologically (for example stablize body
Parameter) or above-mentioned two aspects regulation disease or illness.In other embodiments, " treatment " refers to prevention or delay disease or disease
Breaking-out, generation or the deterioration of disease.
As described herein, term " pharmaceutically acceptable carrier " include any solvent, decentralized medium, coating agents,
Surfactant, antioxidant, preservative (such as antibacterial agent, antifungal agent), isotonic agent, salt, drug stabilizing agent, bonding
Agent, excipient, dispersant, lubricant, sweetener, flavor enhancement, colouring agent, or its composition, these carriers are all affiliated technologies
Known (such as the Remington's Pharmaceutical Sciences, 18thEd.Mack of art personnel
Printing Company, described in 1990, p1289-1329).Except any conventional carrier situation incompatible with active component
Outside, its purposes in treatment or pharmaceutical composition is covered.
Term " study subject " used in the present invention refers to animal.Typically described animal is mammal.It is tested right
As for example also referring to primate (such as the mankind, sex), ox, sheep, goat, horse, dog, cat, rabbit, rat, small
Mouse, fish, bird etc..In certain embodiments, the study subject is primate.In other embodiments, it is described by
It is people to try object.
Term " patient " used in the present invention refers to people (including adult and children) or other animals.In some implementations
In scheme, " patient " refers to people.
Term "comprising" is open language, i.e., including the content specified by the present invention, but be not precluded from otherwise
Content.
" stereoisomer " refers to identical chemical constitution, but the spatially different change of arrangement mode of atom or group
Compound.Stereoisomer includes enantiomter, diastereoisomer, rotamer (rotational isomer), geometric isomer
(cis/trans) isomers, atropisomer, etc..
" enantiomter " refers to that two of a compound can not isomers that is overlapping but being mutually mirror.
" diastereoisomer " refers to have two or more chiral centres and its molecule not alloisomerism of mirror image each other
Body.Diastereoisomer has different physical properties, such as fusing point, boiling point, spectral quality and reactivity.Diastereoisomer is mixed
Compound can be by high resolution analysis operation such as electrophoresis and chromatogram, and such as HPLC is separated.
Term " dynamic isomer " or " tautomeric form " refer to can be built by low energy with different-energy
(lowenergybarrier) constitutional isomer of mutual inversion of phases., can be with if tautomerism is possible (as in the solution)
Reach the chemical balance of dynamic isomer.For example, (also referred to as proton translocation is mutual for proton tautomer (protontautomer)
Tautomeric (prototropictautomer)) include the mutual inversion of phases that is carried out by proton migration, such as keto-enol isomery
Change and imine-enamine isomerizations.Valence tautomerism body (valencetautomer) includes the restructuring by some bonding electrons
Come the mutual inversion of phases carried out.The instantiation of ketoenol tautomerization is pentane -2,4- diketone and the amyl- 3- alkene -2- ketone of 4- hydroxyls
The change of dynamic isomer.Another tautomeric example is phenol-keto tautomerism.One of phenol-keto tautomerism is specific
Example is the change of pyridine -4- alcohol and pyridine -4 (1H) -one dynamic isomer.Unless otherwise noted, the institute of the compounds of this invention
There are tautomeric forms to be within the scope of the present invention.
" pharmaceutically acceptable salt " used in the present invention refers to the organic salt and inorganic salts of the compound of the present invention.Medicine
Acceptable salt is known to us in art on, such as document：S.M.Bergeetal.,describe
pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences,
1977,66:1-19. it is described.The salt that pharmaceutically acceptable nontoxic acid is formed is included, but is not limited to, with amino base
The inorganic acid salt that group's reaction is formed has hydrochloride, hydrobromate, phosphate, sulfate, perchlorate, and acylate, such as second
Hydrochlorate, oxalates, maleate, tartrate, citrate, succinate, malonate, or by being remembered on books document
The other method of load such as ion-exchange obtains these salt.Other pharmaceutically acceptable salts, including adipate, alginic acid
Salt, ascorbate, aspartate, benzene sulfonate, benzoate, bisulphate, borate, butyrate, camphor hydrochlorate, camphor tree
Brain sulfonate, cyclopentyl propionate, digluconate, lauryl sulfate, esilate, formates, fumaric acid
Salt, gluceptate, glycerophosphate, gluconate, Hemisulphate, enanthate, caproate, hydriodate, 2- hydroxyls-second
Sulfonate, lactobionate, lactate, laruate, lauryl sulfate, malate, malonate, mesylate, 2-
Naphthalene sulfonate, nicotinate, nitrate, oleate, palmitate, pectate, persulfate, 3- phenylpropionic acid salt, picric acid
Salt, pivalate, propionate, stearate, rhodanate, tosilate, undecylate, valerate, etc..By suitable
When the obtained salt of alkali include：Alkali metal, the salt of alkaline-earth metal.The present invention is also intended to contemplate the change of any included N group
The quaternary ammonium salt that compound is formed.Water-soluble or oil-soluble or dispersion product can be obtained by quaternization.Alkali metal or alkali
Earth metal salt includes sodium, lithium, potassium, calcium, magnesium, etc..Pharmaceutically acceptable salt further comprises appropriate, nontoxic ammonium, season
Ammonium salt and the amine cation of gegenions formation, such as halide, hydroxide, carboxylate, hydrosulphate, phosphoric acid compound, nitre
Acidulants, C1-8Azochlorosulfonate acid compound and aromatic sulphonic acid compound.
Medicine of the present invention can improve lesion tissue state, and conspicuousness reduction MPO activity and TNF-α, IL- β contain
Amount, reduces the release of inflammatory factor, is expected to be developed into new drug clinically.
Brief description of the drawings
Fig. 1：Normal group colon pathology section (× 100, HE are dyed)；
Fig. 2：Model control group colon pathology section (× 100, HE are dyed)；
Fig. 3：Medicine group colon of the present invention pathology section (× 100, HE are dyed).
Embodiment
Below by way of the description of embodiment, the invention will be further described, but this is not the limit to the present invention
System, those skilled in the art are according to the basic thought of the present invention, and various modifications may be made or improves, but without departing from this
The basic thought of invention, within the scope of the present invention.
Therapeutic effect of the experimental example medicine of the present invention for colitis
Medicine of the present invention：
SD rats 30 are taken, female, 220~240g of weight is randomly divided into 3 groups, respectively Normal group (0.9%
Isometric 0.9% sodium-chloride water solution of sodium-chloride water solution modeling+intraperitoneal injection), model control group (TNBS modelings+abdominal cavity note
Penetrate isometric 0.9% sodium-chloride water solution) and medicine group of the present invention (TNBS modelings+intraperitoneal injection medicine 2.1mg of the present invention
kg-1), every group 10.Rat Fast 24h before modeling, free water.With reference to《Zhou Yanhong, He little Fei, Bai Yuting, wait ginkgo leaf to carry
Take influence [J] the Chinese Pharmacological Bulletins of thing to experimental colitis of rats expression of tumor necrosis factor-alpha, 2007,23 (12):
1605-1609.》, experimental colitis of rats model is set up using TNB (TNBS).Rat is anesthetized with ether
Afterwards, by a diameter of 2.0mm silicone tube from the light and slow insertion 8cm of anus, by 80mgkg rat body weights-1TNBS be dissolved in 50 bodies
Product % ethanol water, is slowly pushed into colon, rat anus is blocked rapidly and 60s is held.0.9% chlorination of Normal group
Sodium water solution replaces modeling liquid, and other operating procedures are identical.Start within the 2nd day after modeling administration, the daily morning 10:It is administered when 00,
Free water is ingested during successive administration 10d, experiment.
Colon's general form
Cut away from colon at anus 8cm, 10% formalin is fixed, routine paraffin wax embedding is cut into slices (4 μm), bush
Essence-Yihong (hematoxylin and eosin, HE) is dyed, micro- Microscopic observation.As a result Fig. 1-3 is seen.As seen from the figure, normally
The rat colon uniform elongate of control group, color is in tender pink colour and color and luster is homogeneous；Model control group Colonic Mucosa of The Rat hyperemia water
Swollen, rotten to the corn, intestinal wall is thickened, with ulcer, and forms Hirschsprung's disease, and mucomembranous surface necrosis, lesion mucous membrane is in dark brown；The present invention
The hyperemia of medicine group intestinal mucosa, oedema, erosion are obviously improved, and have no obvious Hirschsprung's disease, only occur the trace after aphtha healing individually
Mark.
Colon homogenate detection myeloperoxidase (myeloperoxidase, MPO) activity and tumor necrosis factor-alpha
(tumor necrosis factor- α, TNF-α), interleukin-1 ' beta ' (interleukin-1 β, IL-1 β) content
3 sections of 0.5cm intestinal segments are cut in the third office of colon, fatty mesenteric tissue is removed, average two deciles, a copy of it adds
0.1mol·L-1Phosphate buffer prepares 10% and is homogenized, and MPO activity and TNF-α, IL-1 β contents are detected by operating instruction.Knot
Fruit see the table below.
Statistical method carries out data processing using 13.0 editions statistical softwares of SPSS.Continuous data uses mean ± standard
DifferenceRepresent, compare between group and use one-way analysis of variance.With P<0.05 is that difference is statistically significant.
3 groups of rat colon MPO, TNF-α and IL-1 β comparision contents
Compared with Normal group,*1P<0.05,*2P<0.0；Compared with model control group,*3P<0.05
Compared with Normal group, MPO activity and TNF-α, IL- β contents are obvious in the homogenate of model control group rat colon
Increase, show modeling success.Medicine of the present invention can reduce rat colon MPO activity and TNF-α, IL- β contents caused by TNBS and show
The reduction of work property.
MPO is one of enzyme in neutrophil leucocyte azurophilic granule, is proportionate with the order of severity of acute inflammation.This hair
Bright medicine group MPO activity is decreased obviously compared with model control group, shows that medicine of the present invention can mitigate enteron aisle neutrophil infiltration
Acute inflammatory reaction.
In inflammation generating process, it is key factor therein to discharge a large amount of proinflammatory factors, particularly TNF-α and IL- β,
Promote the generation of inflammatory cascade reaction in organismic internal environment.TNF-α is as mediator is started in cytokine network, mainly by activating
Mononuclear macrophage produce, can induce various kinds of cell and produce inflammatory factor, network is formed between cell factor, expand inflammation and connect
Lock reactor causes intestinal mucosal injury, participates in inflammatory reaction and immune response.IL- β are acknowledged as mediating the thin of colitis morbidity
One of intracellular cytokine.IL- β can promote neutrophil infiltration, promote IL-2 expression of receptor thin with other by activating T, B cell
Intracellular cytokine acts synergistically, and promotes neutrophil leucocyte and macrophage activation and degranulation, while promoting inflammatory cell release prostatitis
Parathyrine, thromboxane, platelet activating factor etc., so as to increase the permeability of epithelial cell and endothelial cell.Medicine of the present invention can
To reduce inflammatory factor TNF-α caused by TNBS and IL- β releases, the inflammatory reaction of rat colon caused by reduction TNBS.
Claims (1)
1. purposes of the following compounds in the medicine for preparing treatment colitis：
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| CB03 | Change of inventor or designer information | ||
| CB03 | Change of inventor or designer information |
Inventor after: Zheng Haodong Inventor after: Gan Huarong Inventor before: Tian Fengxiang |
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| TA01 | Transfer of patent application right | ||
| TA01 | Transfer of patent application right |
Effective date of registration: 20170727 Address after: 517 room 4, building 1199, 510000 forest road, Whampoa District, Guangdong, Guangzhou Applicant after: Cloud world Polytron Technologies Inc. Address before: 050035 Shijiazhuang high tech Development Zone, Hebei Province, Tianshan Road, No. 38 Applicant before: Tian Fengxiang |
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Granted publication date: 20170926 Termination date: 20211107 |